New Drug Approvals for Sarcoma in the Last 5 Years.

Sarcoma and locally aggressive connective tissue tumors are a complex group of diseases with a growing number of histotypes in the most recent WHO classification. Most of these tumors are rare (incidence <6/105/y) or ultrarare (<1/106/y). Despite their rarity, sarcomas are often good models for the development of personalized medicine, and a large number of new clinical trials in select histotypes and molecular subsets were reported during the past 5 years, leading to a faster rate of new drug approvals. We analyzed the published literature and the abstracts reported in major congresses dedicated to sarcoma and connective tissue tumor management in the last 5 years. Several targeted therapies, cytotoxic treatments, and immunotherapies have demonstrated activity in dedicated histologic and molecular subtypes of sarcomas. The majority of the studies for ultrarare entities are uncontrolled studies, as a consequence of the rarity of histotypes, but randomized controlled trials were available in the less rare histotypes. Most successful trials were based on biomarker selection, which were often driver molecular alterations, while a large number of ongoing research programs aim to identify biomarkers in parallel to new drug development. Availability of the new agents varies across countries. This article describes the new drugs that made it through to the finish line and new agents with promising activity that are in later stages of investigation in the large family of malignant connective tissue tumors.

Overview of « druggable ¼ alterations by histological subtypes of sarcomas and connective tissue intermediate malignancies.

We summarize herein the literature data about molecular targeted therapies in sarcomas and conjunctive tissue intermediate malignancies. For each clinical setting, the level of evidence, the mechanism of action and the target are described. The two major axes include (i) identification of subgroups of tumors with druggable alteration irrespective of the histological diagnosis (e.g. NTRK), and (ii) druggable target of pathway related to the physiopathology of the tumor: denosumab and bone giant cell tumor, imatinib and soft tissue giant cell tumor, mTOR inhibitor and PECOMA.

Burosumab in tumor-induced osteomalacia: A case report.

Tumor-induced osteomalacia is a rare cause of acquired hypophosphatemia due to the paraneoplastic overproduction of fibroblast growth factor-23. Unlike many causes of osteomalacia, tumor-induced osteomalacia is curable by resection of the offending tumor. If a patient has a tumor that is unidentifiable, unresectable, or makes the decision to forgo surgery, medical treatment is recommended. Burosumab (KRN23) is a fully human monoclonal antibody against fibroblast growth factor-23 that was recently approved for the treatment of X-linked hypophosphatemia. We present a case of tumor-induced osteomalacia due to two somatostatin receptor avid meningiomas. The patient initially was wheelchair bound due to symptoms of diffuse bone and muscle pain with recurrent traumatic and nontraumatic fractures. Serum phosphate was 1.8mg/dL (reference range: 2.4-5.0mg/dL) with no other laboratory or historical cause. Workup revealed two widely separated intracranial meningiomas with typical magnetic resonance imaging characteristics. The duplicity of tumors precluded safe surgery and the potential delay in, or lack of, efficacy using radiosurgery prompted the treatment team to opt for medical treatment. Burosumab was initiated resulting in improvement in pain symptoms and mobility. Serum phosphate normalized. Trials are ongoing to assess the utility of burosumab in the treatment of tumor-induced osteomalacia.

[Bone and calcium metabolism associated with malignancy. Tumor-induced osteomalacia.]

Tumor-induced osteomalacia(TIO)is a paraneoplastic syndrome caused by excessive production and secretion of fibroblast growth factor 23(FGF23)from causative tumors which induces hypophosphatemia and osteomalacia. Mesenchymal benign tumors in bone or soft tissue are the most frequent causes for TIO. The first choice treatment of TIO is complete resection of the responsible tumors. In patients whose tumors cannot be completely removed, phosphate salt and active vitamin D are usually prescribed. The effect of anti-FGF23 monoclonal antibody that inhibits the actions of FGF23 is being tested in clinical trials.

Burosumab: First Global Approval.

Burosumab (Crysvita®; Kyowa Hakko Kirin Co., Ltd. and Ultragenyx Pharmaceutical Inc.) is a fully human monoclonal antibody directed at fibroblast growth factor 23 (FGF23). Excessive FGF23 production has been implicated in various hypophosphataemic diseases. Inhibition of FGF23 by burosumab results in increased renal phosphate reabsorption and increased serum levels of phosphorus and active vitamin D. In February 2018, the EMA granted subcutaneous burosumab conditional marketing authorization for the treatment of X-linked hypophosphataemia (XLH) with radiographic evidence of bone disease in children one year of age and older and adolescents with growing skeletons. In April 2018, the US FDA approved burosumab for the treatment of XLH in adults and children one year of age and older. Multinational phase III trials of burosumab are currently underway in adult and paediatric patients with XLH. Burosumab is also being evaluated in the phase II setting in adults with tumour-induced osteomalacia and epidermal nevus syndrome in the USA, as well as in Japan and Korea. This article summarizes the milestones in the development of burosumab leading to its first global approval in the EU for XLH in paediatric patients.

Occult phosphaturic mesenchymal tumour of femur cortex causing oncogenic osteomalacia - diagnostic challenges and clinical outcomes.

BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes.

Phosphaturic mesenchymal tumors: what an endocrinologist should know.

Tumor-induced osteomalacia (TIO), also known as "oncogenic osteomalacia", is a rare cause of osteomalacia. TIO often has an insidious onset characterized clinically by progressive muscle weakness and bone pain with fractures. The hallmark biochemical finding is a persistent low serum phosphorus concentration due to renal phosphate wasting. The vast majority of cases of TIO result from production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) by a histologically distinctive mesenchymal tumor, termed "phosphaturic mesenchymal tumor" (PMT). Circulating FGF23 induces internalization of renal sodium/phosphate co-transporters resulting in reduced proximal tubular phosphate reabsorption. FGF23 also inhibits production of 1α,25-dihydroxyvitamin D which is inappropriately low or normal in the context of hypophosphatemia. Diagnosis is often delayed owing to the rarity of the condition and an underappreciation for the role of phosphorus as a cause for the constellation of symptoms. Primary treatment for TIO is identification of the offending tumor and surgical removal. However, these tumors are notoriously difficult to find, precluding the opportunity for a curative surgery in many. In such cases, phosphate and calcitriol therapy is used to improve symptoms and heal the osteomalacia. Recently, molecular genetic studies have shown recurrent genetic events in PMT, including the novel fusions FN1-FGFR1 and less commonly FN1-FGF1. These fusion events are hypothesized to result in autocrine/paracrine signaling loops within the tumor, spurring tumorigenesis. This review will cover the clinical features, imaging characteristics, pathologic features, molecular genetic aspects, and therapy of PMT, with a brief discussion of other neoplasms that may cause TIO.

PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse.

BACKGROUND: Immune checkpoint inhibitors have led to a breakthrough in solid tumor immunotherapy, but related studies on musculoskeletal tumors are few, especially for PD-L2. METHODS: We examined expression of three molecular effectors of the PD-1 axis in 234 patients with musculoskeletal tumors, including osteosarcoma, chondrosarcoma, synovial sarcoma, and giant cell tumor. Survival analyses and potential mechanisms were investigated in osteosarcoma per the Gene Expression Omnibus (GEO) and immunohistochemistry analyses. In vivo, humanized mice were used to evaluate the effect of nivolumab on osteosarcoma. RESULTS: PD-L1, PD-L2, and PD-1 expression levels were significantly different between the histologic types of the musculoskeletal tumors. For osteosarcoma, PD-L1 was negatively correlated with prognosis, while PD-1 had a negative correlation tendency with overall survival (OS). Meanwhile, PD-L2 had a positive correlation trend with OS. Nivolumab inhibited osteosarcoma metastasis in humanized mice by increasing CD4+ and CD8+ lymphocytes and the cytolytic activity of CD8 lymphocytes in the lung but did not affect primary osteosarcoma growth. CONCLUSION: We systematically detected the expression patterns of PD-L1, PD-L2, and PD-1 in musculoskeletal tumors for the first time and demonstrated the prognostic roles and underlying mechanisms of PD-1 axis in osteosarcoma. Furthermore, PD-1 blockade could effectively control osteosarcoma pulmonary metastasis in vivo. Therefore, the PD-1 axis may be a potential immunotherapeutic target for metastatic osteosarcoma.

Clinical response of masitinib mesylate in the treatment of canine macroscopic mast cell tumours.

OBJECTIVES: To retrospectively evaluate the clinical response and toxicity associated with masitinib mesylate (Masivet®) treatment of macroscopic mast cell tumours in the dog. METHODS: Retrospective review of medical records of 39 dogs that had undergone treatment with masitinib for macroscopic mast cell tumours. Patient signalment, tumour location, tumour grade, tumour stage, previous treatments, concurrent medications, dose of masitinib, side effects, response, time to tumour progression, survival time and cause of death were documented. Response was assessed according to RECIST criteria. RESULTS: Clinical response was observed in 32 (82·1%) dogs receiving masitinib, with 15 dogs (38·5%) exhibiting a complete response and 17 dogs (43·6%) achieving a partial response. The median time to progression was 79 days (range: 14 to 667 days). Adverse effects were seen in 25 dogs (64·1%) with serum alanine aminotransferase elevation (n=9; 23·1%) and vomiting (n=6; 15·4%) being most common. Median survival time following initiation of masitinib was 159 days (range: 14 to 1339). CLINICAL SIGNIFICANCE: Masitinib appears to be a well-tolerated and effective drug against macroscopic mast cell tumours.

[Oncogenic osteomalacia. Report of two cases]. / Osteomalacia oncogénica. Presentación de dos casos.

Oncogenic osteomalacia is a rare disease. It is caused by a tumor that produces fibroblast growth factor 23, a hormone that decreases the tubular phosphate reabsorption and impairs renal hydroxylation of vitamin D. This leads to hyperphosphaturia with hypophosphatemia and low calcitriol levels. About 337 cases have been reported and we studied two cases; 44 and 70 year-old men who sought medical attention complaining of suffering diffuse bone pain over a period of approximately one year. In both cases, a laboratory test showed biochemical alterations compatible with a hypophosphatemic osteomalacia. In the first case, a soft tissue tumor of the right foot was removed, one year after the diagnosis. The patient was allowed to diminish the phosphate intake, but symptoms reappeared at this time. Eight years later, a local recurrence of the tumor was noted. A complete excision was now performed. The patient was able to finally interrupt the phosphate intake. In the second case, an F-18 fluorodeoxyglucose positron emission tomography, with computed tomography revealed a 2.26 cm diameter hypermetabolic nodule in the soft tissue of the right forefoot. After its removal, the patient discontinued the phosphate intake. Both patients are asymptomatic and show a regular phosphocalcic laboratory evaluation. The histopathological diagnosis was, in both cases, a phosphaturic mesenchymal tumor, a mixed connective tissue variant. This is the prototypical variant of these tumors.

Osteomalacia oncogénica: Presentación de dos casos

La osteomalacia oncogénica es una enfermedad rara. Existen descriptos alrededor de 337 casos. Es ocasionada por un tumor productor del factor de crecimiento fibroblástico 23 (FGF-23), hormona que disminuye la reabsorción tubular de fosfatos y altera la hidroxilación renal de la vitamina D, con hipofosfatemia, hiperfosfaturia y niveles bajos de calcitriol. Se presentan dos pacientes de 44 y 70 años, que consultaron por dolores óseos generalizados de aproximadamente un año de evolución en los que se hallaron alteraciones bioquímicas compatibles con osteomalacia hipofosfatémica. En el primer caso se realizó la resección de una tumoración en tejido celular subcutáneo del pie derecho, un año después del diagnóstico clínico. Luego de la exéresis, se disminuyó el aporte de fosfatos que recibía el paciente, pero reaparecieron los dolores al intentar suspenderlos. Ocho años más tarde, hubo recidiva local de la tumoración por lo que se efectuó resección completa. Después de la misma, se logró suspender el aporte de fosfatos. En el segundo caso, el paciente se estudió con tomografía por emisión de positrones con 18F-fluorodesoxiglucosa, hallando formación nodular hipermetabólica en partes blandas de antepie derecho, de 2.26 cm de diámetro. Luego de su escisión se pudo suspender el aporte de fosfatos. Ambos pacientes se encuentran asintomáticos con indicadores de metabolismo fosfocálcico normales. El diagnóstico anatomopatológico en ambos fue un tumor mesenquimático fosfatúrico, variante mixta del tejido conectivo, la entidad más frecuentemente asociada a la osteomalacia oncogénica.

Oncogenic osteomalacia is a rare disease. It is caused by a tumor that produces fibroblast growth factor 23, a hormone that decreases the tubular phosphate reabsorption and impairs renal hydroxylation of vitamin D. This leads to hyperphosphaturia with hypophosphatemia and low calcitriol levels. About 337 cases have been reported and we studied two cases; 44 and 70 year-old men who sought medical attention complaining of suffering diffuse bone pain over a period of approximately one year. In both cases, a laboratory test showed biochemical alterations compatible with a hypophosphatemic osteomalacia. In the first case, a soft tissue tumor of the right foot was removed, one year after the diagnosis. The patient was allowed to diminish the phosphate intake, but symptoms reappeared at this time. Eight years later, a local recurrence of the tumor was noted. A complete excision was now performed. The patient was able to finally interrupt the phosphate intake. In the second case, an F-18 fluorodeoxyglucose positron emission tomography, with computed tomography revealed a 2.26 cm diameter hypermetabolic nodule in the soft tissue of the right forefoot. After its removal, the patient discontinued the phosphate intake. Both patients are asymptomatic and show a regular phosphocalcic laboratory evaluation. The histopathological diagnosis was, in both cases, a phosphaturic mesenchymal tumor, a mixed connective tissue variant. This is the prototypical variant of these tumors.

In vitro efficacy of doxorubicin and etoposide against a feline injection site sarcoma cell line.

Feline injection site sarcoma (ISS) is a locally invasive tumor, in which surgical treatment is frequently combined with radiation or chemotherapy to improve tumor control. The focus of this study was to evaluate the cytotoxic effects of doxorubicin or etoposide on a feline injection site sarcoma cell line (JB) and to assess the impact of combining these drugs on cell death and cell cycle. Both single agent and combination drug administration increased cell death and significantly reduced the number of viable cells. Cells in G0/G1 were significantly reduced while the G2/M fraction was significantly increased following treatment. Collectively, combining doxorubicin and etoposide at the lower EC yielded comparable results to the EC50 of either drug alone in degree of cytotoxicity, level of apoptosis, and % of cells in G2/M. The results of this study indicate that doxorubicin and etoposide alone and in combination differentially alter ISS cell viability and cycle.

Extracellular signal-regulated kinase 5 and cyclic AMP response element binding protein are novel pathways inhibited by vandetanib (ZD6474) and doxorubicin in mesotheliomas.

Malignant mesothelioma (MM), lung cancers, and asbestosis are hyperproliferative diseases associated with exposures to asbestos. All have a poor prognosis; thus, the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMA) is a tyrosine kinase inhibitor that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, tyrosine kinase inhibitors alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without doxorubicin (Dox) was examined. Van alone reduced total cell numbers in HMESO MM and synergistically increased the toxicity of Dox in HMESO and H2373 cells. Most importantly, we identified two novel cell survival/resistance pathways, ERK5 and cyclic AMP response element binding protein (CREB), that were inhibited by Van and Dox. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox but inhibited by the addition of Van in MM. Data from our study support the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.

[Oncogenic osteomalacia and its symptoms: hypophosphatemia, bone pain and pathological fractures]. / Onkogeniczna osteomalacja czyli hipofosfatemia, bóle kostne i zlamania patologiczne.

Oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i.e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. The clinical course of oncogenic osteomalacia is characterized by bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are usually located in the upper and lower limbs, with half of the lesions primarily situated in the bones. Most of them are small, slow-growing tumors. Their insignificant size and various location coupled with rare occurrence of the disease and non-specificity of clinical symptoms lead to difficulties in reaching a diagnosis, which is often time-consuming and requires a number of additional tests. The average time between the appearance of the first symptoms and the establishment of an accurate diagnosis and the beginning of treatment is over 2.5 years. The aim of this study is to discuss the pathophysiology of disease symptoms, pathomorphology of tumors, diagnostic methods and treatment of oncogenic osteomalacia.

Histology-specific therapy for advanced soft tissue sarcoma and benign connective tissue tumors.

Molecularly targeted agents have shown activity in soft tissue sarcoma (STS) and benign connective tissue tumors over the past ten years, but response rates differ by histologic subtype. The field of molecularly targeted agents in sarcoma is increasingly complex. Often, clinicians must rely on phase II data or even case series due to the rarity of these diseases. In subtypes with a clear role of specific factors in the pathophysiology of disease, such as giant cell tumor of the bone and diffuse-type tenosynovial giant cell tumor, it is reasonable to treat with newer targeted therapies, when available, in place of chemotherapy when systemic treatment is needed to control disease. In diseases without documented implication of a pathway in disease pathogenesis (e.g. soft tissue sarcoma and vascular endothelial growth factor), clear benefit from drug treatment should be established in randomized phase III trials before implementation into routine clinical practice. Histologic subtype will continue to emerge as a critical factor in treatment selection as we learn more about the molecular drivers of tumor growth and survival in different subtypes. Many of the drugs that have been recently developed affect tumor growth more than survival, therefore progression-free survival may be a more clinically relevant intermediate endpoint than objective response rate using Response Evaluation Criteria In Solid Tumors (RECIST) in early phase sarcoma trials. Because of the rarity of disease and increasing need for multidisciplinary management, patients with connective tissue tumors should be evaluated at a center with expertise in these diseases. Participation in clinical trials, when available, is highly encouraged.

Secondary resistance of extra-gastrointestinal stromal tumors to imatinib mesylate: report of a case.

Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate.